CIS is a potent checkpoint in NK cell-mediated tumor immunity

Rebecca B. Delconte, Tatiana B Kolesnik, Laura F. Dagley, Jai Rautela, Wei Shi, Eva M. Putz, Kimberley Stannard, Jian Guo Zhang, Charis En-Yi Teh, Matt Firth, Takashi Ushiki, Christopher E Andoniou, Mariapia A Degli-Esposti, Phillip P Sharp, Caroline E. Sanvitale, Giuseppe Infusini, Nicholas P.D. Liau, Edmond M Linossi, Christopher J Burns, Sebastian CarottaDaniel H.D. Gray, Cyril Seillet, Dana S. Hutchinson, Gabrielle T Belz, Andrew I. Webb, Warren S. Alexander, Shawn S Li, Alex N Bullock, Jeffery J. Babon, Mark J. Smyth, Sandra E. Nicholson, Nicholas D Huntington

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115 Citations (Scopus)


The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.

Original languageEnglish
Pages (from-to)816-824
Number of pages9
JournalNature Immunology
Issue number7
Publication statusPublished - 21 Jun 2016

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